A Supramolecular Stabilizer of the 14‐3‐3ζ/ERα Protein‐Protein Interaction with a Synergistic Mode of Action

Alba Gigante,Federico Gago,Eline Sijbesma,Xiaoyu Hu,Christian Ottmann,Shirley Knauer,Carsten Schmuck,David Bier,Pedro A Sánchez‐Murcia,Sandra Bäcker

doi:10.1002/ange.201914517

Abstract

AbstractWe report on a stabilizer of the interaction between 14‐3‐3ζ and the Estrogen Receptor alpha (ERα). ERα is a driver in the majority of breast cancers and 14‐3‐3 proteins are negative regulators of this nuclear receptor, making the stabilization of this protein‐protein interaction (PPI) an interesting strategy. The stabilizer (1) consists of three symmetric peptidic arms containing an arginine mimetic, previously described as the GCP motif. 1 stabilizes the 14‐3‐3ζ/ERα interaction synergistically with the natural product Fusicoccin‐A and was thus hypothesized to bind to a different site. This is supported by computational analysis of 1 binding to the binary complex of 14‐3‐3 and an ERα‐derived phosphopeptide. Furthermore, 1 shows selectivity towards 14‐3‐3ζ/ERα interaction over other 14‐3‐3 client‐derived phosphomotifs. These data provide a solid support of a new binding mode for a supramolecular 14‐3‐3ζ/ERα PPI stabilizer.

Highlights

Members of the 14-3-3 protein family are regulatory adapter elements in intracellular signaling pathways by means of recognition of proteins that contain phosphorylated Ser/Thr residues like those implicated in the MAPK pathway.[1,2] As a measure of
We report on a stabilizer of the interaction between 14-3-3z and the Estrogen Receptor alpha (ERa)
ERa is a driver in the majority of breast cancers and 14-3-3 proteins are negative regulators of this nuclear receptor, making the stabilization of this protein-protein interaction (PPI) an interesting strategy

Summary

Introduction

Members of the 14-3-3 protein family are regulatory adapter elements in intracellular signaling pathways by means of recognition of proteins that contain phosphorylated Ser/Thr residues like those implicated in the MAPK (mitogen-activated protein kinase) pathway.[1,2] As a measure of. A Supramolecular Stabilizer of the 14-3-3z/ERa Protein-Protein Interaction with a Synergistic Mode of Action

Results

Conclusion